Dibenzothiazefin derivatives

ABSTRACT

Tricyclic compounds of the formula:   WHEREIN: A is -(CH2)m-, -CH CH-, -(CH2)p-O-, -(CH2)p-S-, -(CH2)p-SO2-, -(CH2)p-NR1 or -SO2-NR2- in which m is 1, 2 or 3, p is 1 or 2, R1 is hydrogen or lower alkyl and R2 is lower alkyl: X and Y are hydrogen or halogen: R and R&#39;&#39; are hydrogen or lower alkyl, and N IS AN INTEGER OF FROM 1 TO 12 INCLUSIVE. These compounds possess psychostimulant, antidepressive, analgesic, antitussive, antihistaminic and gastric antisecretory properties.

United States Patent Malen et al. I

r [111 3,821,249 v [451 June 28,1974

[ DIBENZOTHIAZEFIN DERIVATIVES [75] Inventors: Charles Malen, Fresnes; Bernard Danree, St. Germain en Laye;

Jean-Claude Poignant, Wissous, all of France [73] Assignee: Societe en nom collectif Science Union et Cie, Societe Francais de Recherche Medicale, Suresnes, France [22] Filed: Oct. 30, 1972 [21] Appl. No 301,997

Related U.S. Application Data [62] Division of Ser. No. 0l9,503, March 13, 1970, Pat.

[52] U.S. Cl 260/327 B [51 1 Int. Cl C07d 93/42 [58] Field of Search 260/327 B [56] References Cited UNITED STATES PATENTS 3,758,528 9/l973 Malen et al 260/404 Primary ExaminerHenry R. Jiles Assistant ExaminerCecilia M. S. Jaisle Attorney, Agent, or FirmGordon W. Hueschen; John T. Reynolds [57] ABSTRACT Tricyclic compounds of the formula:

F R-N-(CI-hh-COOR wherein:

X and Y are hydrogen or halogen: R and R are hydrogen or lower alkyl, and n is an integer of from 1 to 12 inclusive.

These compounds possess psychostimulant, antidepressive, analgesic; antitussive, antihistaminic and gastric antisecretory properties.

7 Claims, No Drawings DIBENZOTHIAZEFIN DERIVATIVES This is a Division of application Serial No. l9,503, filed March 13, 1970, now US. Patent No. 3,758,528, issued Sept. 11, 1973. v

The present invention provides tricyclic compounds of the general formula I wherein:

-A'is a bridge selected from the following radicals: (CH CH CH-, (CH ),,O,

m is an integer of from 1 to 3 inclusive;

p is an integer selected from 1 and 2;

R, is selected from the group consisting of a hydrogen atom and a lower alkyl radical containing from 1 to 5 carbon atoms inclusive, and

R is a lower alkyl radical containing from 1 to 5 carbon atoms inclusive;

X andY are the same or different and each is selected from the group consisting 'of a hydrogen atom and a halogen atom selected from fluorine, chlorine and bromine atoms;

R and R are the same or different and each is selected from the group consisting of a hydrogen atom and a lower alkyl radical containing from 1 to 5 carbon atoms inclusive in a straight or branched chain; and I n isan integer of from 1 to 12 inclusive.

The .compounds of the general formula I in which R represents a hydrogen atom are amp'hoteric compounds which yield metal salts with bases of the alkali or alkaline earth metals, such, for example, as sodium, potassium or calcium hydroxide, carbonate and bicarbonate, and salts with inorganic or organic acids, such, for example. as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, propionic, maleic, fumaric, methane sulfonic, tartaric, citric, oxalic and benzoic acids. The compounds of general formula I in which R represents an alkyl radical are basic compounds which yield salts with inorganic or organic acids mentioned above. All these salts are included in the present invention.

Furthermore, some compounds of the general formula I possess an asymmetric carbon atom and thus exist in the form of optical isomers. These optical isomers are included in the presentinvention.

The present invention also provides aprocess for preparing the compounds of the general formula I, which comprises condensing a halogenated derivative of general formula ll:

aliphatic w-amino-ester of general formula III: 4

R NH (CH COOR in which R and n have the values given above and R represents a lower alkyl radical containing 1 to 5 carbon atoms, so as to yield the compounds of the general formula I in which R is a lower alkyl radical, and then saponifying the ester so obtained to yield a compound of the general formula I in which R is a hydrogen atom.

The condensation is carried out in a suitable organic solvent, for example, nitromethane, acetonitrile or dimethylformamide, in the presence of an acceptor of the hydracid formed during the reaction. This acceptor may be an excess of the w amino-ester (III), a tertiary amine, a pyridine base, or an alkali or alkaline earth carbonate or bicarbonate. The reaction is generally slightly exothermic and takes place at a temperature preferably within the range of from 20 to C.

The saponification of the resulting ester is carried out either in an akaline aqueous alcoholic medium or in a strongly acid aqueous alcoholic medium.

Thehalogenated starting compounds II have been prepared by methods which are in themselves known starting from the corresponding hydroxylated .compounds, which are either treated with dry hydrochloric acid or with thionyl chloride. These hydroxylated com-.

EXAMPLE 1 7-[dibenzo (a,d) cycloheptadien-S-yl] aminoheptanoic acid hydrochloride 01 n -gnonm-coon cycloheptene in 60 ml of nitromethane and 10.8 g of ethyl ,7-aminoheptanoate in '12 ml of nitromethane were mixed at ambient temperature. The reaction was slightly exothermic. The reaction mixture was left to stand overnight and the solvent was evaporated in vacuo. The residue was taken up in normal hydrochloride acid and the resulting precipitate was filtered off.

10.5 g of crude ethyl 7-[dibenzo (a,d) c'ycloheptadien-5-yl] aminoheptanoate hydrochloride were obtained, of which a sample recrystallized from benzene gave a pure product melting instantaneously at 166 to 168C.

The hydrochloride of the crude ester obtained above was added to 25 ml of 2N hydrochloric acid. The whole was kept under reflux for 2 hours. The material dissolved and a new hydrochloride then reprecipitated. After cooling, the hydrochloride of the crude acid was filtered off, washed with iced water and then recrystallized from distilled water. 5.7 g of 7-[dibenzo (a,d) cycloheptadien--yl] aminoheptanoic acid hydrochloride were obtained, melting instantaneously at 226 to 230C.

EXAMPLES 2 14 ll The derivatives of which substituents and melting points are collected together in the Table below were prepared according to the process described in Example l:

dichloro-dibenzo (b,e) thiepine, melting at l2l-l23- Table 1 Ex A X Y R R n form isolated instantaneous melting point 2 CH CH. H H H H 5 hydrochloride 210C 3 CH -CH H H H H 7 hydrochloride l80 l85C 4 -CH CH H H H H l0 hydrochloride l42 l44C 5 CH. .CH. Cl-2 H H H 6 hydrochloride 180C 6 CH- ,CH Cl-3 H H H 6 hydrochloride 2lOC 7 2 2CH2 H H H H 6 hydrochloride 260C 8 CH CH H H H H 5 free acid lC 9 CH CH H H H (1H,, 6 hydrochloride I58 l60C l0 CH CH H H H C H 7 hydrochloride l50C l l -CH CH H H H C.,H l0 hydrochloride 128 iC EXAMPLE 12 25 C, were obtained. d1 7 chloro dibenzo (he) thiepingl l y]] aminohep 7.2 g of 8,11-d1chloro-d1benzo (b,e) thleplne were tanoic acid hydrochloride Cl CHPS reacted with 9 g of ethyl 7-aminoheptanoate in nitromethane in accordance with the process described in Example 1. 10.9 g of a product containing 99,percent 7 f" g 4 Of ethyl 7-[8-chlorodibenzo 11,8 thiepin-l l-yl] amino- 8 b heptanoate were finally obtained 1n the form of a nond c crystalline gum. 9.9 g of this ester were treated with 60 ml of normal hydrochloric acid and refluxing was con- 9 l O 0 tinued for 2 hours. The whole was evaporated in vacuo. Cl H (011m The residue was taken up 1n 50 ml of acetonltrlle. The r whole was heated under reflux, and then filtered while 2 g of 4-chloro (a-phenylthio) tolulc acid were added hot. The filtered and dried product was then recrystalto a solution of 7.2 g of phosphorus pentoxide, P 0 in lized from distilled water. 6 g of dl 7-[8-chloro-dibenzo 5 ml of phosphoric acid. The reaction mixture was kept 4O (b,e)-thiepin-l l-yl] aminoheptanoic acid hydrochloat 100C for 2 hours whilst stirring. [t was decomposed ride, melting instantaneously at 20 0-210C, were obwith ice and then extracted with benzene. The benzene tained. phase was washed with dilute sodium hydroxide solution and then with water, dried and evaporated. The EXAMPLES 13 T 227 residue was recrystallized from cyclohexane. l g of 8- The derivatives of which the substituents and melting chloro-dlbenzo (b,e) thlepln-l l-one, melting (mlcropolnts are collected together in the Table below were Kofler) at l52l53C, was obtained. prepared according to the process described in Exam- 4.5 g of 8-chloro-dibenzo (b,e) thiepin-l l-one in ple 12. This Table also contains the melting points of ml of methanol were treated with 1.31 g of sodium borthe starting materials used where these are new prodohydride. After the usual treatment, 4 g of the crude ucts: V

Table 2 Ex A X Y R R n form instantaneous melting point melting point isolated melting point of the of the Corresponding corresponding chlorinated hydroxyl derivative derivative 13 -CH., o- H H H C2H5 5 hydrolC not isolated chloride in the pure state 14 CH20- C1-2 H H 6 hydro- 204C 122 126C 138 140C chloride .15 -CH,-o- (l-3 H H 6 hydro- 190C 80- 84C 113 ll5C Chloride l6 -CH2O- F-?. H H H 6 hydro- 206C 154 158C 76 78C chloride 17 CH,-O- H C1 8 H H 6 hydro- 180C [15C 104 108C chloride V I8 -CH,-s- Cl 3 H CH, H 5 free 142C not isolated acid in the pure State Table 2 Continu ed Ex A X Y R R. n form instantaneous melting point melting point isolated melting point of the ofthe corresponding corresponding chlorinated hydroxyl derivative derivative 19 CH- S Cl-3 H H H 6 hydro- 210C not isolated chloride in the pure state 20 CH,-S Cl-3 Cl-9 H H 6 hydro- 210C 100- 102C 160 162C chloride 21 CH S- Cl-2 H H H 5 hydro- 200 203C 104 106C 158 160C chloride 22 CH S Cl-3 H H H 5 hydro- 181 182C not isolated 140 142C I chloride in the pure state 23 -CH -S- Cl-2 H H H 6 hydro- Y chloride 24 CH S C1-3 H H H 6 hydro- 200C chloride 25 CH SO C1-3 H H H 5 hydro- 206C V chloride 26 -CH2CH2S H H H H 5 hydro- 210212C chloride 27 CH CH H H H H 6 hydro- 247 248C chloride EXAMPLE 28 amlno-hexanolc acld were thus obtained, meltlng lnd1-6-[10,10-dioxo-l l-methyl dibenzo (cf) thiazepin 1,2)-5-yl]-aminohexanoic acid A solutio riof 8 g (0.05 mol) of freshly distilled ethyl 6-aminocaproate in 10 ml of nitromethane were added all at once to a well-stirred suspension of 7.3 g (0.025 mol) of 5-chloro-l0,lO-dioxo-l l-methyl-dibenzo (qf) thiazepine 1,2) in 40 ml of distilled nitromethane. A slight exothermic reaction was observed with the temperature rising to 35C and the halogenated derivative dissolving completely. Stirring was then continued for minutes. The reaction mixture was evaporated in vacuo. The residue was taken up in 30 ml of water. The insoluble oil which separated out was extracted with benzene and the benzene phase was washed with water and then dried' over sodium sulphate. The solvent was evaporated in vacuo and 10.7 g of crude oily ethyl d1 6-[ 10,10-dioxo-1 l-methyldibenzo (c,f) thiazepin (1,2)-5-y1] aminohexanoate were obtained, in which the content of pure product determined by measurement with perchloric acid in an acetic acid medium is 95 percent.

10.4 g of this ester thus obtained were treated with l g of sodium hydroxide dissolved in 60 ml of ethanol and 10 ml of water. The mixture was kept under reflux for .45 minutes and then evaporated in vacuo. The residue was taken up in 30 ml of water and the aqueous solution was extracted with ether. The aqueous phase was cautiously acidified to pH 4.5 5. The acid which precipitated was extracted with chloroform. The chloroform phase was washed and dried, and then evaporated. The 7.3 g of crude acid thus obtained was recrystallized from 10 m1 of ethanol and 5.5 g of d1 6-[ 10,10- dioxo-l l-methyl-dibenzo (cJ) thiazepin (1,2)-5-yl] stantaneously at l 18C.

EXAMPLE 29 Ethyl d1 3-[lO,10-dioxo-1l-methyl-dibenzo (cf) thiazepin (1,2)-5-yl] aminopropionate hydrochloride Working as in Example 28 and starting from 11.6 g of 5-chloro-lO-dioxo-1 l-methyl-dibenzo (cj) thiazepine (1,2) and 9.4 g of ethyl B-amino-propionate, 15 g of d1 3-[ l0-dioxo-l l-methyl-dibenzo (cj) thiazepin 1,2)-5-yl]aminopropionate were obtained, containing 94 percent of pure product as determined by measurement with perchloric acid.

15 g of this crude ester were dissolved in ml of anhydrous'ether and treated with a solution of hydrochloric acid in anhydrous ether. The hydrochloride precipitated and was filtered off, washed with ether and dried. 15.5 g of crude ethyl dl 3-[10-dioxo-1 l-methyldibenzo (cJ) thiazepin-( 1,2)-5-yl] aminopropionate hydrochloride were obtained, which on recrystallisation from water yielded 12.3 g of a pure product, melting instantaneously at 210C.

EXAMPLE 30 Sodium 7-[8-chloro-10-dioxo-l l-methyl-dibenzo (c,f) thiazepin-( 1,2 )-5-yl] aminoheptanoate out /SOr-N A solution of 27.6 g (0.16 mol) of freshly distilled ethyl 7-amino-heptanoate in 40 ml of nitromethane was added all at once and with mechanical stirring to a suspension of 26.2 g (0.08 mol) of 5,8-dichloro-10-dioxo- 1 l-methyl-dibenzo (c'J) thiazepine (1,2) in 120 ml of nitromethane. The whole was heated to 55C for 30 minutes, the solvent was then evaporated in vacuo and the residue was taken up in water. The crude ester was extracted with ether. After evaporation of the ether 36 g of crude ester were obtained, and 30 g (0.065 mol) thereof were treated under reflux with a solution of 2.8 g (0.07 mol) of sodium hydroxide in 75 ml of ethanol and 25 ml of water. After one hours refluxing, the alcohol was evaporated in vacuo. The residue was taken up in 150 ml of water. The mixture was twice extracted with 75 ml of chloroform and the aqueous phase was evaporated in vacuo. The sodium salt was then dissolved in 150 ml of chloroform, the solution was dried over sodium sulphate and the product precipitated with anhydrous ether.

EXAMPLES 32 48 The derivatives of which the substituents and melting points were collected in the Table below were prepared according to the process described in Example 28 to 31. The 5-chloro-l0,l0-dioxo-l l-C to C -alkyldibenzo (c thiazepines (1,2) which are the starting materials used in Examples 28 to 48 are described in our French Patent No. 1,566,191.

TABLE 3 Instantaneous melting Ex. A X Y R R 71 Form isolated point, C.

32 (3H3 H H H H 1 Free acid 220 C O2-N- 33 Same as above... H H H CzHs 1 Hydrochloride hemihydratem 180 341" d H H CH3 Na 3 Dihydrate 150 H H H 5 Free acid hemihydrat 115 H H H 5 Hydrochloride 210 01-8 H H 5 Free acid 50-70 Cl-S H H 5 Hydrochloride dihydrate 150 (31-8 H Na 5 Sodium salt hemihydrate" Cl-7 H Na 5 Sodium salt tetrahydratc 160 C1-8 H Na 5 Sodium salt c. 170

01-8 OH; H 5 Free acid 130 (31-8 H Na 10 Sodium salt 254 C2H5 H BT-B C4H9 H 6 "H-610 S O2-N 46 (3 H; Br3 H H C3111 3 Hydrochloride S O2-N 47 C HS Cl l H CH3 H 5 -d0 48 Sameasabove... 01-4 11 H CH: 6 s d0 The salt was filtered off, washed with ether and dried at 50C. 13 g of sodium 7-[8-chloro-10-dioxo-l 1- methyl-dibenzo (c,f) thiazepin (1,2)-5-yl] aminoheptanoate, melting with decomposition at about 180C, were obtained.

EXAMPLE 31 d1 8-[8-chloro-10,10-dioxo-1 l-methyl-dibenzo (cf) thiazepin (1,2)-5-yl] aminooctanoic acid hydrochloride.

9.35 g (0.050 mol) of freshly prepared ethyl 8- aminooctanoate were added all at once and while stirring to a suspension of 8.2 g (0.025 mol) of 5,8- dichlorol0, l0-dioxo-1 l-methyl-dibenzo, (cj) thiazepine (1,2) in 60 ml of nitromethane. The whole was doses of 5 to 20 mg/kg, increase the threshold of pain perception from 30 to 170 percent.

The antitussive activity was studied by the method of Gooswald R. [Arzfschg 8, 550 (1958)]. The new compounds, administered by subcutaneous route in the guinea-pig at doses of 2 to 20 mg/kg, decrease from 40 to percent the cough of the animals submitted to a 40 percent citric acid aerosol for 4 minutes.

The new compounds inhibit the bronchospasm provoked by intravenous injection of histamine in the guinea-pig [Konzett and Rossler: Arch. Exp. Path. U.

9 Phar. 195, 7 l, 1940)]. The spasm is inhibited from 26 to 75 percent by intravenous doses of 2.5 to mg/kg.

The gastric antisecretory activity was studied by the method of H. Shay et al. [Gastroenterology 5, 43 (1945)]. It was observed that the new compounds inhibit the gastric secretion in rat at doses of 5 to 50 mg/kg by intraperitoneal route. The decrease of the volume of gastric secretion in treated animals varies from to '70 percent compared with the untreated animals 4 hours after the ligature of pylorus.

The hereabove described properties, as well as the low toxicity, allow the use of the new compounds in therapy, especially in the treatment of psychoneurotic disorders, pain, cough and gastric hypersecretion.

The present invention also includes pharmaceutical compositions for oral, rectal or parenteral administration, containing a compound of the general formula I or a physiologically tolerable salt thereof, in admixture or conjunction with a suitable pharmaceutical carrier, such, for example, as distilled water, glucose, lactose, talc, starch, magnesium stearate and cocoa butter.

Doses may vary from 10 to 100 mg l to 5 times a day.

A. Tricyclic compounds of the formula N tokens-9 9 wherein X and Y are each selected from the group consisting of hydrogen, fluorine, chlorine and bromine;

R is selected from the group consisting of hydrogen, lower alkyl having from 1 to 5 carbon atoms;

R is a lower alkyl having from 1 to 5 carbon atoms;

R is selected from the group consisting of hydrogen, lower alkyl having from 1 to 5 carbon atoms and a monovalent cation derived from a physiologically tolerable base; and

n is an integer of from 1 to 12 inclusive; and

B. the physiologically tolerable acid addition salt when R is hydrogen or a lower alkyl radical having from 1 to 5 carbon atoms.

2. A compound of claim 1 which is d] 7-[8-chloro- 10, lO-dioxo-l l-methyl-dibenzo (cj) thiazepin-( l ,2)- 5-yl] aminoheptanoic acid.

3. A compound of claim 1 which is propyl dl 4-[3- bromol0, 1 O-dioxo- I l-propyldibenzo(c,f) thiazepin l,l )-5-yl] aminobutyrate.

4. A compound of claim 1 which is (1] 6-[8-chloro- 10,10-dioxo-l l-methyl-dibenzo(c,/) thiazepin 1,2 5-yl] aminohexanoic acid.

5. A compound of claim 1 which is sodium dl 6-[8- chlorol O, 1 O-dioxo-l l-methyl-dibenzo (cj) thiazepin l,2)-5-yl] aminohexanoate salt.

6. A compound of claim 1 which is the hydrochloric acid addition salt of dl 6-[2,8-dichloro-l0,10-dioxo-l lmethyl-dibenzo(c,f) thiazepin l ,2)-5-yl] aminohexanoic acid.

-7. A compound of claim 1 which is sodium dl l l-[8- chloro-lO, lO-dioxo-l l-methyl-dibenzo (cj) thiazepin l ,2)-5-yl] aminoundecanoate salt. 

2. A compound of claim 1 which is dl 7-(8-chloro-10,10-dioxo-11-methyl-dibenzo (c,f) thiazepin-(1,2)-5-yl) aminoheptanoic acid.
 3. A compound of claim 1 which is propyl dl 4-(3-bromo-10,10-dioxo-11-propyldibenzo(c,f) thiazepin (1,1)-5-yl) aminobutyrate.
 4. A compound of claim 1 which is dl 6-(8-chloro-10,10-dioxo-11-methyl-dibenzo(c,f) thiazepin (1,2)-5-yl) aminohexanoic acid.
 5. A compound of claim 1 which is sodium dl 6-(8-chloro-10,10-dioxo-11-methyl-dibenzo (c,f) thiazepin (1,2)-5-yl) aminohexanoate salt.
 6. A compound of claim 1 which is the hydrochloric acid addition salt of dl 6-(2,8-dichloro-10,10-dioxo-11-methyl-dibenzo(c,f) thiazepin (1,2)-5-yl) aminohexanoic acid.
 7. A compound of claim 1 which is sodium dl 11-(8-chloro-10,10-dioxo-11-methyl-dibenzo (c,f) thiazepin (1,2)-5-yl) aminoundecanoate salt. 